Polyethylene glycol–phosphatidylethanolamine conjugate (PEG–PE)-based mixed micelles: Some properties, loading with paclitaxel, and modulation of P-glycoprotein-mediated efflux

• Published in: International journal of pharmaceutics 2006-06, Vol.315 (1), p.148-157
• Main Authors: Dabholkar, Rupa D., Sawant, Rishikesh M., Mongayt, Dimitriy A., Devarajan, Padma V., Torchilin, Vladimir P.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Bile Acids and Salts; Biological and medical sciences; Caco-2 Cells; Colonic Neoplasms - drug therapy; Colonic Neoplasms - pathology; General pharmacology; Humans; Hydrogen-Ion Concentration; Medical sciences; Micelles; Mixed micelles; P-glycoprotein; Paclitaxel; Paclitaxel - administration & dosage; Paclitaxel - pharmacokinetics; PEG–PE; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Phosphatidylethanolamines; Polyethylene Glycols; Solubility; TPGS
• ISSN: 0378-5173; 1873-3476
• DOI: 10.1016/j.ijpharm.2006.02.018

Mixed micelles prepared of poly(ethylene glycol)2000–phosphatidyl ethanolamine conjugate (PEG 2000–PE) and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) in 1:1 molar ratio have been investigated. Micelle formation was confirmed by NMR spectroscopy. CMC of the micelles was found to be 1.5 × 10 −5 M. Poorly soluble anti-cancer drug paclitaxel (PCL) was efficiently solubilized in 15 nm non-toxic PEG–PE/TPGS micelles. PCL entrapment was quite stable with only about 20% of the incorporated drug released from micelles after 48 h at 37 °C. In addition, PCL-containing PEG 2000–PE/TPGS micelles were stable in vitro under various conditions modeling the physiological ones, in particular, at low pH values and in the presence of bile acids, which is especially important for their possible oral administration. Fluorescently labeled micelles demonstrated time-dependent internalization by human colon adenocarcinoma cell line, Caco-2. The internalization of PEG 2000–PE/TPGS micelles loaded with P-glycoprotein (P-gp) substrate, rhodamine-123 (RH-123), opposite to the internalization of the free RH-123, was not influenced by the inhibition of the P-gp pump with verapamil hydrochloride, which assumes a P-gp-independent micelle internalization.